Inherited metabolic disorders involving the...

In the name of godInherited metabolic disorder(IMD)

involving the eyeA.Medghalchi.M.D

Associated professor of pediatrics ophthalmology

1398

OCT OF RETINA

Eye and IMDs The eye is the fourth most common system

affected by genetic disease.

More than 200 loci for genetic ocular diseases have been mapped.

Ocular manifestation of IMD

Symmetrical bilateral involvement

Sever visual impairment around 2m Easily recognized in galactosemia Delayed diagnosis in peroxisomal disease

Fundus may be normal but abnormal VEP & ERG

Ocular abnormality of metabolic disordersConjunctivaCorneaLensRetinaOptic nerveOcular motility

What is a metabolic disease? Small molecule disease

ProteinCarbohydrate Lipid

Nucleic Acids

Organelle disease

LysosomesMitochondria Peroxisomes

Cytoplasm

Disorders of Amino Acid Metabolism

AlbinismCystinosisHomocystinuria Sulfite oxidize deficeincyHyperornithinemia (Gyrate Atrophy) Tyrosinemia type IIHyperlysinemia

Albinism

Refractive errorsReduced visual acuity Iris transillumination defectsNystagmus StrabismusAlbino fundosAbnormal nerve fiber crossing

Albinism


AlbinismCystinosisHomocystinuria Sulfite oxidize deficeincyHyperornithinemia (Gyrate Atrophy) Tyrosinemia TYPE IIHyperlysinemia

Cystinosis Defective transport of cystine across lysosomal

membranes

Corneal crystal accumulation

Pigmentary retinopathy


AlbinismCystinosisHomocystinuria Sulfite oxidize deficeincyHyperornithinemia (Gyrate Atrophy) Tyrosinemia TYPE IIHyperlysinemia

HOMOCYSTINURIA Absence of cystathionine b-synthetase (the enzyme

that converts homocysteine to cystathionine)Systemic features:

Fair skin with coarse hair

Osteoporosis

Mental retardation (nearly 50%)

Seizure disorder

Marfanoid habitus

Thromboembolic episode

Homocystinuria

Ocular manifestations Progressive myopia Ectopia lentis Increased IOP Retinal detachment Optic atrophy

Disorders of Amino Acid MetabolismAlbinismCystinosisHomocystinuria Sulfite oxidize deficeincyHyperornithinemia (Gyrate Atrophy) Tyrosinemia type IIHyperlysinemia

SULFITE OXIDASE DEFICIENCY Defect in sulfur metabolismSystemic features: Seizures Brain dysfunction (encephalopathy) Spastic quadriplegia Movement problems Dystonia Choreoathetosis Ataxia Ectopia lentis

Disorders of Amino Acid Metabolism Albinism Cystinosis Homocystinuria Sulfite oxidize deficeincy Hyperornithinemia (Gyrate Atrophy) Tyrosinemia type II Hyperlysinemia

Hyperornithinemia(Gyrate Atrophy)

AR inheritted chorioretinal dystrophy Deficiency of the activity of the mitochondrial matrix

enzyme, ornithine aminotransferaseOcular Manifestations Myopia Night Blindness Cataract Chorioretinal Atrophy


Albinism Cystinosis Homocystinuria Sulfite oxidize deficeincy Hyperornithinemia (Gyrate Atrophy) Tyrosinemia type II Hyperlysinemia

Tyrosinemia type II Autosomal recessive disorder caused by mutations in the

tyrosine aminotransferase Pseudodendritic keratitis Hyperkeratosis of the palms and soles Mental retardation


Albinism Cystinosis Homocystinuria Sulfite oxidize deficeincy Hyperornithinemia (Gyrate Atrophy) Tyrosinemia type II Hyperlysinemia

Hyperlysinemia

Extremely rare autosomal recessive

Mental retardation Ectopia lentis

Disorder of CarbohydrateMetabolism

Diabetes mellitusGalactosemiaGlycogen storage diseaseglucose-6-phosphate dehydrogenaseVon Gierke's disease

Diabetes

Lids and conjunctiva Conjunctival aneurysms Reduced blood flow Macro-vessel dilatation Increased risk of infection Recurrent styes Blepharoconjunctivitis

Xanthelasma

A. Diabetes :Lid and Conj

Diabetis :Cornea

Superficial punctate keratitis Recurrent corneal erosions Poor healing of corneal epithelium

Diabetis: lens Senile cataract True diabetic cataract

Diabetis :retina

Disorder of CarbohydrateMetabolism

Diabetes mellitusGalactosemiaGlycogen storage diseaseglucose-6-phosphate dehydrogenaseVon Gierke's disease

B. Galactosemia Deficit in the activity of galactose-l-hosphate

uridyl transferase

Cataract is related to the accumulation of galactitol in the lens

“oil drop” appearance

Disorders of lipid metabolismNiemann-pick diseaseFabry’s diseaseGaucher diseaseMetachromatic leukodystrophyGangliosidosis GM2 gangliosidosis type 1 or Tay-Sachs disease

GM2 gangliosidosis type 2 or Sandhoff disease

GM1 gangliosidosis type 1 or Landing's disease

Niemann-Pick Disease Type A Acute neuronopathic form A cherry-red macula in 50% of infants Brownish discoloration of anterior lens capsule

Chery red spot

Niemann-Pick Disease Type BChronic form without nervous system

involvementCherry-red spot

Niemann-Pick Disease Type C

Chronic neuropathic form May have vertical ophthalmoplegia No cherry-red spot Optic atrophy

Fabry’s disease

Ocular changes Conjunctiva: Increased vessel

tortuosity and aneurysms Cornea: verticillata. Retina :Increased tortuosity of

vesselesLens : faint spoke-like lines opacity

at the posterior lens capsule

Fabry’s disease

GAUCHER DISEASE Type 1 Most common Chronic, non-neuronopathic disorder of adult onset Ocular feature : Brownish piguecula-like masses containing gaucher cells Retina :gaucher cell

GAUCHER DISEASE,Type 2Acute neuronopathic infantile form

Persistent retroflexion of the head and signs of seudobulbar palsy

The classic Gaucher triad consists Trismus

Strabismus

Opisthotonus

GAUCHER DISEASE, Type 3 Subacute, juvenile neuronopathic form

Ocular feathers: Ocular apraxia Corneal opacification

Metachromatic leukodystrophy (MLD)

MLD is also known as “diffuse brain sclerosis

Disorder of myelin metabolismAccumulation of cerebroside sulfate in the

CNS and peripheral nervesLate infantile, juvenile, and adult forms are

recognized, based on the age of onset

Metachromatic leukodystrophy (MLD) Austin’s disease Multiple sulfatase deficiency (MSD) is a rare

form of late-infantile MLD

Ophthalmologic features : Skew deviation Optic atrophy

Retinal degeneration Cherry-red spot.

Gangliosidosis GM2 gangliosidosis type 1 or Tay-Sachs disease GM2 gangliosidosis type 2 or Sandhoff disease GM1 gangliosidosis type 1 or Landing's disease

Eye manifestation: cherry red spot

Disorder of glycoproteindegradation Mannosidosis Fucosidosis Sialidosis

Mannosidosis Deficiency of enzyme mannosidase Storage of N-linked oligosaccharides in tissues urineOphthalmologic manifestations: Type I (Infantile) : Lens opacity in posterior cortex Type II (Juvenile) : Punctate opacity throughout lens Strabismus Pallor and blurring of optic disc Retinal degeneration

Mannosidosis

Disorder of glycoproteindegradation Mannosidosis Fucosidosis Sialidosis

Fucosidosis Deficiency of enzyme α-fucosidase Accumulation of glycoproteins, glycolipids, and

oligosaccharides containing fucosidesOcular feature : Vascular tortousities Conjunctival vessels are tortous,with microaneurysms Retinal veins are dilated and tortuous

Disorder of glycoproteindegradation

Mannosidosis Fucosidosis Sialidosis Schindler disease

Sialidosis Rare lysosomal storage disease Deficiency of the enzyme α-Nacetylneuraminidase two forms : type 1 type 2

Sialidosis Type 1 Milder form Cherry-red spot Myoclonus syndrome Opsoclonus:rapid, multi-directional eye

movements Myoclonus:quick, involuntary muscle jerks Ataxia: uncoordinated movement

Sialidosis type 2

Ophthalmologic findings Infantile-onset sialidosis Myoclonus is present. Macular cherry-red spot Punctate lens opacities

Lysosomal storage diseaseMPS

Ocular manifestations: Progressive corneal clouding Retinal Pigmentary Degeneration Diminished or extinguished electroretinogram Optic nerve head swelling Optic atrophy Glaucoma

Lipoprotein and LipidDisorders Familial Hypercholesterolemia Cerebrotendinous xanthomatosis

Lipoprotein and LipidDisorders

Xanthelesma Arcus Senalis

Miscellaneous

Wilson's diseaseMenkes disease

Wilson's diseaseKayser-Fleischer ring Due to deposition of copper in Descemet's membrane Band of golden to greenish-yellow,bronze or brownish

hue in the peripheral of cornea

Sunflower cataract Occurs in only 15% to 20% of affected persons

Fine deposits beneath the anterior and posterior lens capsule, forming a disc like opacity axially

The opacities do not interfere with vision

Wilson's disease

Menkes disease an X-linked recessive disorder of copper

metabolism

Systemic feathers:

steely hair

progressive neurologic deterioration

lax skin

arterial degeneration

Menkes diseaseOcular manifestations

Hypopigmentated fundus

Decrease in the nerve fibers of the optic nerve

Increase in the glial elements

Attenuation or tortuosity of the retinal arterioles

Thanks for your attention

Thanks for your attention

Conjunctiva

cystinosis Fabry GM1

Mucolipidosis tyrosenimia

Cystinosis

fabry

cystinosis

gaucherCalciumdeposit

Introduction

The field of inherited metabolic disorders (IMDs) is often thought to have been born in 1902

Archibald Garrod published his first paper describing alkaptonuria and first coined the term ‘inborn error of metabolism’.

Early diagnosis

Early diagnosis is crucial for three reasons.

IMDs are rapidly progressive and cause irreversible damage early in the course of the disease.

the treatment can often be effective, if commenced early and long-term outcome may be improved.

correct early diagnosis helps in genetic counselling.

fabry

cystinosis

gaucherCalciumdeposit

cystinosis Fabry

GM1

Mucolipidosis tyrosenimia

clobuma

AlBini

sm

Mar phan

DeGeNeration

cystinosis

diabet diabet

Kearn sayerKSS Gyrate

atrophy

Optic atrophy Optic neuritis

Eye and IMDs

Classifications of inherited metabolic disorders

Eye and IMDs

Effects are due:

to toxic accumulations of substrates before the block

intermediates from alternative metabolic pathways

defects in energy production and utilization caused by a deficiency of products beyond the block.

Environmental factors

degree of accumulation of toxic substances before metabolic block diet, undercurrent infection, fasting drugs, and so on.

Eye and IMDs

Recognition of IMDs is important as it is quite common in incidence.

Early diagnosis is important, as in most cases, dietary restriction and early therapy prevents onset of disability.

Prenatal diagnosis using amniocentesis and chorionic villus sampling may help to reduce the burden due to IMDs.

Ocular manifestations of IMDs

patient presents with a known IMD and eye defect appears as a known manifestation of the disease

patient comes to the outpatient department primarily with ocular abnormalities and an IMD is suspected.

Ocular manifestations of IMDs

symmetrical bilateral involvement

Severe visual impairment is around 2 m old.

Anomalies of the eye are easily recognized as in cataracts in galactosaemia.

In others as in peroxisomal diseases,fundoscopic examination may be normal in the neonatal period, whereas ERG and VEP are abnormal.

IMDs involving the cornea The cornea may loss :

transparency

optical function

structural integrity.

Inherited disorders of metabolism can lead to accumulation of substances, which may become evident as opacities in the corneal epithelium (Fabry’s disease), stroma( cystinosis), or Descemet’s membrane (Wilson’s disease).

disorders of protein formation may cause structural abnormalities of the cornea.

Accumulation of a metabolic pathway product in the cornea leads to staining of the cornea in several IMD

IMDs involving the cornea

The mucopolysaccharidoses (MPSs) are a heterogeneous group of disorders of errors in the carbohydrate metabolism

severe ocular involvement (corneal opacification, retinal degeneration,and optic atrophy)

characterised by accumulation of glycosaminoglycanswithin multiple organ systems.

Dermatan and keratan sulphate are deposited in the cornea and the degree of storage in keratocyte determines the degree of corneal clouding.

LYSOSOMAL STORAGE DISEASES MPSOcular manifestations :

progressive corneal clouding

retinal pigmentary degeneration

optic atrophy

Papilledema is a frequent finding, occurring in one third

hydrocephalus that results from meningeal thickening with the storage material

narrowing of the scleral canal, as a result of posterior scleral thickening with mucopolysaccharide accumulation.

Acute and chronic glaucoma may be seen in MPS IH, IS, and IH-S

Excess dermatan and keratan sulfates appear in the cornea

heparan sulfate accumulates in the retina and central nervous system

the storage of heparan sulfate in the retina, a retinal pigmentary degeneration associated with night blindness develops.


Fabry’s disease is an X-linked glycosphingolipid storage disorder that is caused by the deficient activity of lysosomal a-galactosidase A, resulting in accumulation of glycolipids, mainly globotriaosylceramide,

Ocular findings :

Engorged conjunctival vessels

congested retinal vessels

corneal opacities

cortical cataract.

.

IMDs involving the corneaWilson’s disease

Wilson’s disease is an inborn error of copper metabolism, having an autosomal recessive inheritance with a mutation in the ATP7B gene encoding a membrane bound copper-transporting ATPase.

Its defect leads to increased copper deposition due to impaired biliary copper excretion.

Ocular findings:

sunflower cataract

pigmented corneal rings ,Kayser-Fleischer (K-F) rings, due to copper deposit in the descmet membrane

Sun flower cataract

IMDs involving the corneaWilson’s disease Treatment is effective if diagnosis occurs before the onset of life-threatening

symptoms.

Drugs used for the initial treatment of Wilson’s disease include penicillamineand trientine.

These act by chelation or binding of copper, causing increased urinary excretion and rapidly reducing the copper content in the body.

Tetrathiomolybdate is another chelating drug that will soon be approved by the FDA for initial treatment of Wilson’s disease.

For long-term care, zinc acetate is preferred, which acts by blocking the absorption of copper in the intestinal tract.

This action depletes accumulated copper and prevents its re-accumulation.

A major advantage of zinc therapy is its lack of serious side effects. In some cases, the condition is diagnosed at the stage of acute liver failure and involvement of the central nervous system (CNS).

When this happens, a liver transplant is required in most cases.


Fish eye disease with partial lecithin carnitine acyl transferase(LCAT) deficiency and low HDL cholesterol levels (due to mutation of LCAT gene) and familial hypercholesterolaemia (with mutation of LDL-receptor gene

elevated levels of LDL cholesterol) may lead to corneal opacities and hence, early detection is warranted to check further damage.

Cystinosis is a rare autosomal recessive metabolic disorder in which nonprotein cystine accumulates within cellular lysosomes owing to a defect in lysosomal cystine transport.

The pathognomonic ocular manifestation of cystinosis is the deposition of distinctive iridescent crystals in the cornea.

Ocular symptoms include:

glare, photophobia

decreased corneal sensation,

mild decrease in vision.

IMDs involving the lens

In galactosaemia, the deficiency of the enzyme (galactose-1-phosphate uridyl transferase) responsible for the breakdown of galactose, leads to build-up of galactose,.

The lens is avascular in nature, receiving its nutrients from aqueous humour.

Most of the glucose metabolism is by anaerobic glycolysis.


In absence of the enzyme (galactose-1- phosphate uridyltransferase), galactose is reduced by aldose reductase to galactitol. Polyol accumulation causes cataract due to increase in intracellular fluid causing lens swelling increased membrane permeability and electrolyte abnormalities.

Galactitol is toxic to the lens, causing opacification due to lens swelling shift of water into the lens and disruption of lens structure.

Dietary restriction after screening is beneficial.

Early identification and elimination of galactose from diet reverses growth failures, renal or liver dysfunction, and has better prognosis.


Peroxisomal disorders are associated with cataract

Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids (CDCAs) is impaired

A defect in hydroxylation of the cholesterol side chain that impairs oxidative cleavage has been identified.

laboratory findings include elevated plasma levels of cholestanol and bile alcohols and increased urinary excretion of bile alcohol glucuronides with diminished biliaryconcentrations of CDCA.

Cataracts, progressive neurological symptoms, and mild pulmonary insufficiency are unique features that distinguish CTX from other xanthomatous disorders.

Treatment of CTX with CDCA, a bile acid, will arrest, but generally will not reverse the frequently devastating neurological deterioration seen in these patients.

Xanthomatous tendon deposits have been reported to regress with CDCA therapy.

Medical therapy, therefore, should be instituted at the time of diagnosis, and family members should be screened for subclinical disease


Treatments by oral administration of CDCA alone,3-hydroxy-3-methylglutaryl CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs

have been attempted for patients with CTX

The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels.

In all patients, the progression of disease was arrested, but dramatic effects on clinical manifestations,xanthoma, and electrophysiological findings could not be found after the treatment of these drugs.

IMDs involving the lensEctopia lentis

Marfan’s syndrome is an inherited disorder of the connective tissue. It is characterised by skeletal and cardiac abnormalities, aortic aneurysms, and ectopia lentis.

The biochemical defect is a mutation on the fibrillin gene.

It is inherited as an autosomal dominant trait.

Lens subluxation is due to microfibril abnormalities of the lens capsule in Marfan’s syndrome.

Subluxation is bilateral, symmetrical, and upward.

The dislocation may be complete, with the lens within the vitreous cavity.

Iridodonesis (tremulousness of the iris) may occur from non-support of the overlying iris by the lens.

Axial length of the globe is increased leading to axial myopia. Retinal detachment is common.

Glaucoma may be result of angle anomaly or may be associated with lens subluxation.

marfan


Homocystinuria. Homocystinuria is a metabolic disorder due to deficiency of the enzyme cystathionine b-synthase producing increased urinary homocysteine and methionine.

It has an autosomal recessive inheritance.

The lens dislocation in homocystinuria commonly occurs inferiorly.

Early detection by screening helps prevent complications by withholding methionine from diet and adding cysteineand large doses of vitamin B6.

The zonular fibres are composed of glycoprotein with high concentration of sulphurcontaining amino acids, which explains their susceptibility to abnormal formation in IMDs of sulphur metabolism


sulphite oxidase and molybdenum cofactor deficiency.

leading to sulphocysteinuria as S-sulpho-L-cysteine accumulates in the lens.

Lens membrane is rich in cholesterol, which helps in normal maintenance of the lens.

Disorders of cholesterol biosynthesis may be associated with opacities of the crystalline lens.

Ehler-Danlos syndrome is one of the inheritable connective tissue disorders due to defect in synthesis of collagen type I and III.

ocular findings:

Keratoconus

fragility of the eye,

marfanoid habitus.

IMDs involving the retina There are over 400 known inherited diseases in which the retina is

substantially involved in the disease process.

Retinitis pigmentosa (RP, prevalence 1 of 4000)33 is a set of hereditary retinal dystrophies, characterised by pigment deposits in the fundus and progressive death of photoreceptors, always associated with the alteration of retinal pigment epithelium and retinal degeneration.

Genetic heterogeneity of the typical non-syndromic form

(rod–cone dystrophy) is extensive: autosomal dominant,autosomal recessive ,X-linked

Most cases are due to a mutation in gene for rhodopsin or the gene for peripherin, a glycoprotein located in photoreceptor outer segment.

IMDs involving the retina

Menke’s disease :

A mutation in a copper-transporting ATP7A gene

low serum copper levels, low ceruloplasmin levels and retinal degeneration, mental retardation, hypopigmentation,and unusual hair (‘kinky’).

Patients with IMDs of lipid metabolism like Zellweger’s syndrome (peroxisome biogenesis disorders),


Refsum’s disease (deficiency of phytanic acid oxidase) and mitochondrial b-oxidation defects exhibit retinal degeneration.

Two rare forms of RP, associated with

the Bassen-Kornzweig’s syndrome

Patients with Bassen-Kornzweig syndrome cannot efficiently transport fat-soluble vitamins from the intestine to the plasma.

Treatment of a patient with large doses of vitamin A at an early stage resulted in reversal of the ERG to normal within 24 h.

Vitamin E also has been advocated to prevent progression of this retinal degeneration


Patients with Refsum’s disease have an elevated serum phytanic acid resulting from a deficiency of phytanic acid oxidase.

This fatty acid accumulates in the retinal pigment epithelium, leading to photoreceptor cell degeneration.

Treatment with a low-phytol, lowphytanic acid diet has resulted in the lowering of serum phytanic acid and stabilisation of retinal function.


Gyrate atrophy of the choroid and retina is a rare autosomal recessive disorder characterised by progressive metabolic, retinal, and choroidal degeneration due to photoreceptor degeneration caused by the deficiency of the pyridoxal phosphate-dependent, nuclear-encoded, mitochondrial matrix enzyme ornithine d-aminotransferase

Extreme hyperornithinemia is universal in this disease.

Its absence necessitates a search for another diagnosis.

All body fluids measured to date (whole blood, plasma, cerebrospinal fluid (CSF), aqueous humour, and urine) have been found to contain 10–20 times the normal levels of ornithine.

As a result,excessive ornithine build-up causes the retinal thinning


Currently, this condition can only be treated with aminoacid tablets and a very low protein diet with limited fruits and vegetables and 42000 cal a day fromcarbohydrates and fats.

Some patients cannot maintain this diet, and they need other treatment.

One possible alternative is to replace the defective gene with one that functions normally, by gene therapy, which is currently under clinical trials.


Neuronal ceroid lipofuscinoses) is the general name for a family of at least eight genetically separate neurodegenerative disorders that result from excessive accumulation of lipopigments (lipofuscin) in the body’s

Juvenile NCL (JNCL, Batten disease), with a prevalence of 1 in 100 000, usually arises between 4 and 10 years of age

the first symptoms include considerable vision loss due to RP, with seizures, psychological degeneration, and eventual death in the mid- to late-20s


To diagnose Batten’s disease/NCL, the neurologist needs the patient’s medical history and information from various laboratory tests.

One of the tests is skin/tissue sampling under electron microscope.

The powerful magnification of the microscope helps the doctor spot

typical NCL deposits.

These deposits are found in many different tissues, including the skin, muscle, conjunctiva,and others.

These deposits take on characteristic shapes,depending on the variant under which they are said to occur; fingerprint profiles are typically found in JNCL.

Electrical studies of the eyes, which include visual evokedresponsesand ERGs, can detect various eye problems common in childhood Batten’s disease/NCLs.


A recent development in diagnosis of Batten’s disease NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile disease

This is a quick and easy diagnostic test.

Currently, there is no widely accepted treatment that can cure, slow down, or halt the symptoms of NCL, other

than supportive therapy.

Gene therapy is under trial for patients with Batten’s disease. NCL is currently under trial to test the effectiveness of bone marrow/neural stem cell transplants for this condition.

IMDs involving the retinacherry red spot

The term ‘cherry red spot’ describes the ophthalmoscopic appearance of the retina in neurometabolic disorders such as Tay-Sach’s disease

This fundus appearance also accompanies other neuronal lipid-storage disorders,including Sandhoff’sdisease (GM2 type II),gangliosidosis GM1 type I and GM2 type III, Niemann-Pick’s disease, sialidosis types I and II, Farber’s disease,mucolipidosis III, and metachromatic leukodystrophy and (central retinal artery occlusion.

The colour of the fovea, however,results from the pigment epithelium and choroid.

The absence of ganglion cells at the fovea gives rise to red spot surrounded by white diseased cells


The various tones of normal pigmentation in the fovea, which lacks ganglion cells, contrast with the surrounding macular region of the retina, in which intracellular accumulation of metabolic products results in opacification during the neural disease process.

Thus, the ‘cherry red spot’ could appropriately be renamed the ‘perifoveal white patch.’

Most patients with MPSs also exhibit macular cherry red spot.

In MPSs, the abnormal metabolic products would be toxic to the retina. In other diseases, the pathogenesis of retinal involvement remains to be clarified.

IMDs involving the optic nerve

Leber’s hereditary optic neuropathy (LHON) or Leber’s optic atrophy is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision

this affects predominantly young adult males. Mitochondrial inheritance was first confirmed in 1988 with the identification of a mitochondrial DNA (mtDNA) point mutation at nucleotide position in the NADH dehydrogenase subunit 4 gene in nine pedigrees with a

Leber’s hereditary optic neuropathy


LHON is associated with three different point mutations of mtDNA affecting nucleotide positions These mutations are estimated to account for

8–25, 50–60, and 10% of LHON pedigrees, respectively.

The incidence of each mutation is reported to be race dependent.

Mitochondrial diseases affect most severely those tissues that have the greatest requirements for oxidative phosphorylation, such as the photoreceptors


Costeff’s optic atrophy syndrome or type III 3-methylglutaconic aciduria, an IMD of leucine metabolism, is a neuro-ophthalmologic syndrome that consists of early onset bilateral optic atrophy and lateonset spasticity, extrapyramidal dysfunction, and cognitive deficit.

Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased.

Krabbe’s disease is an autosomal recessive sphingolipidosis caused by deficient activity of the lysosomal hydrolase


galactosylceramide b-galactosidase due to mutation in the gene mapped to chromosome band 14q31

This enzyme degrades galactosylceramide, a major component of myelin, and other terminal b-galactosecontaining sphingolipids, including psychosine(galactosylsphingosine).

Increased galactosylceramide and psychosine levels are believed to lead to widespread destruction of oligodendroglia in the CNS and to subsequent demyelination.

Hallmarks of the classic infantile form are irritability, hypertonia, hyperaesthesia, and psychomotor arrest, followed by rapid deterioration,elevated protein levels in the CSF, neuro-radiologic evidence of white matter disease, cortical blindness, optic atrophy, and early death


Metachromatic leukodystrophy is a demyelinating storage disease caused by deficiency of the lysosomalenzyme arylsulphatase A, leading to the accumulation of galactosylceramide-3-o-sulphate (sulphatide) in the central and peripheral nervous systems.

Patients with MLD show the storage of metachromaticcomplex lipids in the RGCs and in the optic nerve, leading to optic atrophy.

The physiopathological process leading to neuronal cell degeneration and apoptosis in the optic nerve involves accumulation of undegraded sulphatides but also secondary abnormalities (storage/ mislocalisation of unrelated lipids, inflammatory processes).

IMDs involving the optic nerve Gaucher’s disease is a lysosomal storage disorder caused by a recessively

inherited deficiency of glucocerebrosidase activity, causes an accumulation of sphingolipid glucosylceramide in cells of the reticulo-endothelial systems.

Ocular manifestations of Gaucher’s disease :

infiltration of the retina, conjunctiva, and uvea

visual loss

eye movement disorders.

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